Protein-bound derivatives of platinum complexes containing cyclobutane1,1-dicarboxyllate ligands

ABSTRACT

The invention concerns low-molecular platinum complexes containing cyclobutane-1,1-dicarboxylate ligands that contain a protein-binding group.

The invention concerns low-molecular platinum complexes ofcyclobutane-1,1-dicarboxylate ligands which contain a protein-bindinggroup, their production and use.

Carboplatin (diammine platinum(II)-cyclobutane-1,1-dicarboxylate) is ananti-neoplastic platinum(II) complex that is used to treat variouscancer diseases (Woloschuk, D. M. et al., Drug Intell. Clin. Pharm.1988, 22, 843-849). Carboplatin differs from the structurally relatedcisplatin (cis-diammine dichloroplatinum(II)) in that the chloroligandsare replaced by a chelating cyclobutane-1,1-dicarboxylate ligand whereinchanges in pharmacokinetics result as well as in a toxicity profile thatis different from cisplatin (Lokich, J., Cancer Invest. 2001, 19,756-760). However, therapies with carboplatin is accompanied byside-effects (Go, R. S. et al., J. Clin. Oncol. 1999, 17, 409-422). Inorder to improve the side-effect profile and the efficacy of cytostaticagents, it has already been proposed that protein-binding formulationsshould be developed which couple in vivo to endogenous serum proteinsand in this manner represent macromolecular transport forms of theactive substances (Kratz, F. et al., Am. Assoc. Cancer Res. 2001, 42,138-139, Kratz, F. et al., J. Med. Chem. 2000, 43, 1253-1256).

The object of the invention is to create protein-binding derivatives ofcarboplatin which have fewer undesired side-effects and a higherefficacy towards tumor tissue.

This object is achieved according to the invention by low-molecularcarboplatin derivatives of the general formula I

in which R=2H,

—(CH₂)_(i)— (i=2 or 3), X=or NH, Y=O, S or 2H, n=0 to 5, m=0 to 6 and PMis a protein-binding group.

The compounds according to the invention are composed of an anti-tumoralcis-configured platinum(II) complex and a heterobifunctionalcross-linker. This structure is elucidated in more detail in thefollowing:

The anti-tumoral platinum complex is a derivative of an active substancehaving the general formula II

in which

R=2H, —(CH₂)_(i)— (i=2 or 3)X═OH or NH₂. It differs from the clinical standard carboplatin in that ahydroxy or amino group is present on the cyclobutane ring and optionallyin that chelating amine ligands such as trans-1,2-diaminocyclohexane,cis-1,2-diaminocyclohexane, ethylene diamine or 1,3-diaminopropane arepresent.

The heterobifunctional cross-linker is a carboxylic acid derivative oran alcohol containing a protein-binding group of the general formula III

in which

-   Y=2H, O or S-   n=0 to 5-   m=0 to 6-   PM=a protein-binding group.

The protein-binding group (PM) is preferably selected from a2-dithiopyridyl group, a halogen acetamide group, a halogen acetategroup, a disulfide group, an acrylic acid ester group, a monoalkylmaleicacid ester group, a monoalkylmaleaminic acid amide group, anN-hydroxy-succinimidyl ester group, an isothiocyanate group, anaziridine group or a maleinimide group. The maleinimide group is aparticularly preferred protein-binding group.

Compounds according to the invention are obtained formally by condensingthe active substance derivative with the cross-linker. Hence there is anester bond, an amide bond, a thioester bond, a thioamide bond, an etherbond or an amine bond between the active substance derivative and thecross-linker.

The platinum complexes according to the invention are preferablyprepared by reacting a cyclobutane-1,1-dicarboxylic acid derivative ofthe general formula IV

in which

-   X═O or NH-   Y═O, S or 2H-   m=0 to 5-   n=0 to 6-   and PM denotes a protein-binding group, with a platinum complex of    the general formula V    in which-   R═2H,    —(CH₂)_(i)— (i=2 or 3)    -   R′=2 NO₂, SO₂ or CO.

For the reaction the platinum complex can for example be dissolved inwater and admixed with the cyclobutane-1,1-dicarboxylic acid derivativeor an alkali or alkaline earth metal salt of thecyclobutane-1,1-dicarboxylic acid derivative. The reactions areexpediently carried out at temperatures between 0° C. and 50° C. inwhich case the reaction time is normally between 1 and 24 hours. Theproduct can be isolated by common methods such as crystallization,chromatography on silica gel or reversed phase chromatography(preparative HPLC).

According to a preferred embodiment, an aqueous solution of acis-diaminoalkyl platinum(II) dinitrate complex or cis-diammineplatinum(II) dinitrate is reacted with a cyclobutane-1,1-dicarboxylicacid derivative which has a maleinimide group and an oligo(ethyleneglycol) backbone at a pH between 5 and 6. The platinum complexesobtained in this manner are preferably purified by column chromatographyon silica gel or by reversed phase chromatography (see examples 5, 6 and9). Platinum complexes obtained in this manner have an excellentwater-solubility.

The cyclobutane-1,1-dicarboxylic acid derivatives having a maleinimidegroup and an oligo(ethylene glycol) backbone that are preferably usedfor the complex formation can be prepared in a four-step synthesisstarting with bis(4-methoxy-benzyl)malonate and1,3-dibromo-2-tert.-butyldimethylsiloxypropane:

In the first step bis(4-methoxybenzyl)malonate is dialkylated with1,3-dibromo-2-tert.-butylsiloxypropane which results in a cyclobutanering system.

This reaction is preferably carried out in an aprotic polar solvent suchas dioxane or DMF using bases such as potassium hydride, sodium hydrideor sodium hexamethyldisilazide at temperatures of >100° C. Under theseconditions the reaction time is typically 48-120 hours (see example 1).

In the second step the tert.-butyldimethylsilyl protecting group iscleaved by methods that are familiar to a person skilled in the artpreferably using tetrabutyl-ammonium fluoride in tetrahydrofuran (seeexample 2).

In the third step the 3-hydroxy group of the cyclobutane ring ofbis(4-methoxybenzyl)-3-hydroxycyclobutane-1,1-dicarboxylate isesterified with a maleinimidocarboxylic acid of the general formula VIa.

in which

-   n=0 to 5-   m=0 to 6.

In this step the reagents that are preferably used to activate thecarboxyl group of the cross-linker are N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide,(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphateor 2-chloro-1-methylpyridinium iodide with addition of conventionalcatalysts or auxiliary bases such as trialkylamines, pyridine,4-dimethylaminopyridine (DMAP) or hydroxybenzotriazole (HOBt). Thereaction is expediently carried out in a polar organic solvent,preferably in dichloromethane, N,N-dimethylformamide andtetrahydrofuran. The reactions are expediently carried out attemperatures between −10° C. to room temperature, in which case thereaction period is normally between 3 and 48 hours.

According to a preferred embodimentbis(4-methoxybenzyl)-3-hydroxycyclo-butane-1,1-dicarboxylate is reactedwith a maleinimidocarboxylic acid which has an oligo(ethylene glycol)backbone, using 2-chloro-1-methylpyridinium iodide (see examples 3 and7) to form a compound of the general formula VII.

In the fourth step the 4-methoxybenzyl protecting group is cleaved offwith trifluoroacetic acid and anisole at 0° C. (see examples 4 and 8).

An important feature of the platinum complexes according to theinvention is that they bind rapidly and covalently to serum proteins viathe protein-binding group which generates a macromolecular transportform of the active substance. It is known that serum proteins such astransferrin, albumin and LDL have a higher uptake into tumor tissue(Kratz F.; Beyer U. Drug Delivery 1998, 5, 281-299) so that they can beused within the scope of the invention as endogenous carriers forcytostatic agents. Circulating human serum albumin (HSA) which is themain protein component of human blood having an average concentration of30 to 50 g/l (Peters T. Adv. Protein Chem. 1985, 37, 161-245) and has afree cysteine group (cysteine 34 group) on the surface of the proteinthat is suitable for binding thiol-binding groups such as maleinimidesor disulfides (WO 00/76551), is a particularly preferred serum protein.

The protein-binding platinum complexes according to the invention can beadministered as drugs either parenterally or preferably intravenously.For this purpose the platinum complexes according to the invention areprovided as solutions, solids or lyophilisates, optionally usingstandard auxiliary agents. Such auxiliary agents are for examplepolysorbates, glucose, lactose, mannitol, dextrans, citric acid,tromethamol, triethanolamine, aminoacetic acid and/or syntheticpolymers. The administered complexes then react with serum proteins toform the transport form.

The new platinum complexes can also be reacted extracorporeally withserum proteins e.g. with an amount of albumin, blood or serum providedfor infusion.

Protein-bound platinum complexes according to the invention havedifferent pharmacokinetics compared to conventional low-molecularcomplexes and accumulate in tumor tissue due to their macromolecularcharacter. The cyclobutane-1,1-dicarboxylate ligand that is bound in alabile manner is cleaved by an intracellular hydrolytic reaction whichreleases aquo, hydroxy or mixed aquohydroxy complexes as activecomponents. In experimental studies on animals these protein-bindingplatinum complexes were more effective than the clinical standardcarboplatin (see example 10).

The invention is elucidated in more detail by the following examples inconjunction with the figures. The figure shows a graph of the results ofan animal experiment with a substance according to the inventioncompared to carboplatin on the basis of a change in the tumor volume.

EXAMPLE 1 Preparation ofbis(4-methoxybenzyl)-3-tert.-butyldimethyl-siloxycyclobutane-1,1-dicarboxylate(PMB-CB-OTBS)

Bis(4-methoxybenzyl)malonate (6.00 g, 17.4 mmol) is added dropwisewithin 30 minutes to a suspension of potassium hydride (35% in mineraloil) (2.10 g, 18.29 mmol) in 20 ml anhydrous dioxane under an inert gasatmosphere. It is allowed to stir for a further 15 min at roomtemperature, 1,3-dibromo-2-tert.-butyldimethylsiloxypropane (6.08 g,18.29 mmol) is added and it is heated overnight under reflux. Potassiumhydride (35% in mineral oil) (2.10 g, 18.29 mmol) is slowly added as asuspension in 10 ml dioxane to the reaction mixture which is cooled toroom temperature. It is subsequently stirred for three further daysunder reflux. The potassium bromide that forms is filtered over Celite,the solvent is removed in a vacuum and the residue is purified by columnchromatography (silica gel, ethyl acetate/isohexane 1:10). 2.78 gPBM-CB-OTBS (31% of theory) is obtained as a colourless oil.

EXAMPLE 2 Preparation ofbis(4-methoxybenzyl)-3-hydroxycyclobutane-1,1-dicarboxylate (PMB-CB-OH)

A solution of PMB-CB-OTBS (2.69 g, 5.23 mmol) in 25 ml anhydrous THF isadmixed with tetrabutylammonium fluoride (2.47 g, 7.85 mmol) and stirredfor 15 min at room temperature. Subsequently the solvent is removed in avacuum and the residue is purified by column chromatography (silica gel,ethyl acetate/isohexane 1:1). 1.85 g PMB-CB-OH (88% of theory) isobtained as a colourless oil which slowly crystallizes.

EXAMPLE 3 Preparation ofbis(4-methoxybenzyl)-3-(6-maleinimido-4-oxacaproyl)cyclobutane-1,1-dicarboxylate(PMB-CB-1-Mal)

A solution of PMB-CB-OH (1.97 g, 4.91 mmol), 6-maleinimido-4-oxacaproicacid (1.57 g, 7.37 mmol) and triethylamine (2.04 ml, 8.64 mmol) isadmixed with 2-chloro-1-methylpyridinium iodide (1.88 g, 7.37 mmol) in30 ml anhydrous dichloromethane and stirred for three hours at roomtemperature. It is diluted with 140 ml dichloromethane, washed each timetwice with 80 ml in hydrochloric acid, 80 ml water and once each timewith 80 ml sodium chloride solution (saturated) and dried over magnesiumsulfate. Subsequently the solvent is removed in a vacuum and the residueis purified by column chromatography (silica gel, chloroform/methanol200:1). 2.89 g PMB-CB-1-Mal (99% of theory) is obtained as a colourlessoil.

EXAMPLE 4 Preparation of3-(6-maleinimido-4-oxacaproyl)cyclobutane-1,1-dicarboxylic acid(COOH-CB-1-Mal)

A solution of PMB-CB-1-Mal (2.76 g, 4.63 mmol) and anisole (7.57 ml,69.5 mmol) is admixed with 10 ml trifluoroacetic acid in 50 ml anhydrousdichloromethane at 0° C. and stirred for two hours at 0° C. Subsequentlythe solvent is removed in a vacuum and the residue is purified by columnchromatography (silica gel, chloroform/methanol 20:1). 1.28 gCOOH-CB-1-Mal (78% of theory) is obtained as a colourless syrup.

EXAMPLE 5 Preparation oftrans-(R,R/S,S)-cyclohexane-1,2-diaminoplatinum(II)-[3-(6-maleinimido-4-oxacaproyl)cyclobutane-1,1-dicarboxylate](DACH-Pt-CB-1-Mal)

A solution of COOH-CB-1-Mal (271 mg, 762 μmol) in 5 ml water is added toan aqueous solution of [Pt trans-DACH](NO₃)₂ (300 mg, 692 μmol) which iscooled to room temperature, the latter being obtained by heating (50°C.) the platinum complex with 60 ml water. The reaction mixture isadjusted to pH 5.5 with 0.1 M KOH and stirred for three hours at roomtemperature in the dark. Subsequently the solvent is removed in a vacuumand the residue is purified by column chromatography (silica gel,ethanol). 291 mg DACH-Pt-CB-1-Mal (61% of theory) is obtained as acolourless solid.

¹H-NMR (CD₃OD):

δ=0.97-1.29 (m, 4H, cyclohexyl-H), 1.38-1.56 (m, 2H, cyclohexyl-H),1.81-1.96 (m, 2H, cyclohexyl-H), 2.19-2.36 (m, 2H, cyclohexyl-H), 2.42(t, J=5.9 Hz, CH ₂COO), 2.60-2.79 (m, 2H, CH ₂CHOR), 3.27-3.41 (m, 2H,CH ₂CHOR), 3.46-3.66 (m, 6H, NCH ₂, OCH ₂), 4.67-4.86 (m, 1H, CHOR),6.76 (s, 2H, C(O)CH═CHCO)

¹³C-NMR (CD₃OD):

δ=25.51, 33.30 (cyclohexyl), 35.92 (CH₂COO), 38.17 (NCH₂), 39.80/40.09(CH₂CHOR), 51.35 (C(COOH)₂), 63.81/63.86 (cyclohexyl-NH₂), 65.66 (CHOR),67.22, 68.65 (OCH₂), 135.50 (C(O)CH═CHCO), 172.52, 172.80 (C(O)CH═CHCO,CH₂ COO), 180.41, 180.61 (C(COOH)₂)

ESI-MS (4.0 kV, MeOH):

m/z (%) 663.0 ([M+1]⁺, 100)

EXAMPLE 6 Preparation of diammineplatinum(II)-[3-(6-maleinimido-4-oxacaproyl)cyclobutane-1,1-dicarboxylate]((NH₃)₂-Pt-CB-1-Mal)

A solution of COOH-CB-1-Mal (538 mg, 1.51 mmol) in 5 ml water is addedto an aqueous solution of [(NH₃)₂Pt](NO₃)₂ (485 mg, 1.37 mmol) which iscooled to room temperature, the latter being obtained by heating (50°C.) the platinum complex with 90 ml water. The reaction mixture isadjusted to pH 5.5. with 0.1 M KOH and stirred for three hours at roomtemperature in the dark. Subsequently the solvent is removed in a vacuumand the residue is purified by column chromatography (silica gel,ethanol). 263 mg (NH₃)₂-Pt-CB-1-Mal (33% of theory) is obtained as acolourless solid.

ESI-MS:

m/z (%) 581.8 ([M]⁺, 100)

EXAMPLE 7 Preparation ofbis(4-methoxybenzyl)-3-(15-maleinimido-4,7,10,13-tetroxapentadecanoyl)cyclobutane-1,1-dicarboxylate(PMB-CB-4-Mal)

A solution of PMB-CB-OH (1.154 g, 2.881 mmol),15-maleinimido-4,7,10,13-tetroxapentadecanoic acid (1.49 g, 4.32 mmol)and triethylamine (1.20 ml, 8.64 mmol) in 20 ml anhydrousdichloromethane is admixed with 2-chloro-1-methylpyridinium iodide (1.10g, 4.32 mmol) and stirred for three hours at room temperature. It isdiluted with 80 ml dichloromethane, washed each time twice with 50 ml 1n hydrochloric acid, 50 ml water and once with 50 ml sodium chloridesolution (saturated) and dried over magnesium sulfate. Subsequently thesolvent is removed in a vacuum and the residue is purified by columnchromatography (silica gel, ethyl acetate). 1.93 g PMB-CB-4-Mal (92% oftheory) is obtained as a colourless oil.

EXAMPLE 8 Preparation of3-(15-maleinimido-4,7,10,13-tetroxapentadecanoyl)cyclobutane-1,1-dicarboxylicacid (COOH-CB-4-Mal)

A solution of PMB-CB-4-Mal (1.94 g, 2.66 mmol) and anisole (4.35 ml,39.9 mmol) in 50 ml anhydrous dichloromethane is admixed with 10 mltrifluoroacetic acid at 0° C. and stirred for two hours at 0° C.Subsequently the solvent is removed in a vacuum and the residue ispurified by column chromatography (silica gel, chloroform/methanol10:1). 1.15 g COOH-CB-4-Mal (89% of theory) is obtained as a colourlesssyrup.

EXAMPLE 9 Preparation oftrans-(R,R/S,S)-cyclohexane-1,2-diaminoplatinum(II)-[3-(15-maleinimido-4,7,10,13-tetroxapentadecanoyl)cyclobutane-1,1-dicarboxylate](DACH-Pt-CB-4-Mal

A solution of COOH-CB-4-Mal (217 mg, 445 μmol) in 5 ml water is added toan aqueous solution of [Pt trans-DACH](NO₃)₂ (175 mg, 405 μmol) which iscooled to room temperature, the latter being obtained by heating (50°C.) the platinum complex with 30 ml water. The reaction mixture isadjusted to pH 5.5 with 0.1 M KOH and stirred for three hours at roomtemperature in the dark. It is subsequently concentrated by evaporationin a vacuum to about 5 ml and the precipitate is centrifuged. Thesupernatant is purified by preparative HPLC (Nucleosil® 100-7-C18 column(250×15 mm), water/acetonitrile 80:20+0.05% TFA, flow rate: 20 ml/min,retention time: about 20 min). After removing the solvent in a vacuumand crystallizing the residue by adding about 1 ml 2-propanol, 60 mgDACH-Pt-CB-4-Mal (19% of theory) is obtained as a colourless solid.

¹H-NMR (D₂O calibrated with acetone δ≡2.20 ppm):

δ=0.98-1.35 (m, 4H, cyclohexyl-H), 1.44-1.62 (m, 2H, cyclohexyl-H),1.94-2.06 (m, 2H, cyclohexyl-H), 2.28-2.48 (m, 2H, cyclohexyl-H), 2.66(t, J=6.0 Hz, CH ₂COO), 2.80-2.93 (m, 2H, CH ₂CHOR), 3.34-3.50 (m, 2H,CH ₂CHOR), 3.54-3.84 (m, 18H, NCH ₂, OCH ₂), 4.93 (‘p’, J=7.1 Hz, 1H,CHOR), 6.85 (s, 2H, C(O)CH═CHCO)

¹³C-NMR (D₂O, calibrated with acetone):

δ=24.30, 32.22 (cyclohexyl), 34.91 (CH₂COO), 37.37 (NCH₂), 38.54/38.72(CH_(2 CHOR),) 50.71 (C(COOH)₂), 63.05/63.09 (cyclohexyl-NH₂), 65.37(CHOR), 66.52, 68.02, 69.73, 69.97, 70.01 (OCH₂), 134.86 (C(O)CH═CHCO),173.39, 174.11 (C(O)CH═CHCO, CH₂CCOO), 180.30, 180.47 (C(COOH)₂)

¹⁹⁵Pt-NMR(D₂O): δ=−311

IR (KBr): ν=3448 (ss, b), 2934 (w, b), 1709 (ss), 1627 (s), 1353 (m),1094 (ss, b), 696 (w) cm⁻¹

ESI-MS (4.0 kV, MeOH): m/z (%) 816.9 ([M+Na]⁺, 100)

C₂₇H₄₁N₃O₁₂Pt [794.71]

elemental analysis: calculated: C, 40.81% H, 5.20% N, 5.29% found: C,39.88% H, 5.16% N, 5.08%

EXAMPLE 10 Efficacy of DACH-Pt-CB-1-Mal In Vivo

The biological data shown in FIG. 1 make it clear that the in vivoefficacy of DACH-Pt-CB-1-Mal is increased compared to carboplatin.

Animals: naked mice Tumor model: MaTu (mammary carcinoma)

Treatment: DACH-Pt-CB-1-Mal (75 and 100 mg/kg) and carboplatin (100mg/kg) once on day 7, carboplatin (75 mg/kg) on each of days 7 and 14;i.v. (carboplatin and derivatives each in 0.15 0.3 ml glucose phosphatebuffer pH 6.5).

1. Platinum complex of the general formula I:

in which

R=2H, —(CH₂)_(i)— (i=2 or 3); X=O or NH; Y=O, S or 2H; m=0 to 5; n=0 to6; PM denotes a protein-binding group.
 2. Platinum complex as claimed inclaim 1, characterized in that PM is a maleinimide group, a2-dithiopyridyl group, a halogen acetamide group, a halogen acetategroup, a disulfide group, an acrylic acid ester group, a monoalkylmaleicacid ester group, a monoalkylmaleaminic acid amide group, anN-hydroxysuccinimidyl ester group, an isothiocyanate group or anaziridine group which can be optionally substituted.
 3. Platinum complexas claimed in claim 2, characterized in that PM is a maleinimide groupwhich can be optionally substituted.
 4. Platinum complex as claimed inclaim 3, characterized in that m<2 and n=to
 4. 5. Platinum complex asclaimed in claim 4, characterized in that X=O and Y=O.
 6. Process forproducing platinum complexes as claimed in claim 1, characterized inthat a cyclobutane-1,1-dicarboxylic acid derivative of the generalformula IV

in which X=O or NH Y=O, S or 2 H m=0 to 5 n=0 to 6 and PM denotes aprotein-binding group, is reacted with a platinum complex of the generalformula V

in which

R=2H, . . . —(CH₂)_(i)— (i=2 or 3) R′=2 NO₂, SO₂ or CO.
 7. Process asclaimed in claim 6, characterized in that thecyclobutane-1,1-dicarboxylic acid derivative of the general formula IIis obtained by reacting a 4-methoxybenzyl-protectedcyclobutane-1,1-dicarboxylic acid derivative of the general formula VII

in which X=O or NH Y=O, S or 2H m=0 to 5 n=0 to 6 and PM denotes aprotein-binding group, with trifluoroacetic acid and anisole.
 8. Processas claimed in claim 7, characterized in that thecyclobutane-1,1-dicarboxylic acid derivative of the general formula VIIis obtained by reacting bis(4methoxybenzyl)-3-hydroxycyclobutane-1,1-dicarboxylate with aheterobifunctional cross-linker of the general formula VI

in which n=0, 1 m=1 to 6 and PM denotes a protein-binding group, in thepresence of carboxylic acid activation reagents.
 9. Process as claimedin claim 8, characterized in that N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide or(benzotriazole-1-yloxy)tris(dimethylamino)phosphoniumhexafluoro-phosphate and most preferably 2-chloro-1-methylpyridiniumiodide are used as carboxylic acid activation reagents.
 10. Process asclaimed in claim 8, characterized in thatbis(4-methoxybenzyl)-3-hydroxycyclobutane-1,1-dicarboxylate is reactedwith a maleinimidocarboxylic acid of the general formula VIa

in which n=0, 1 m=1 to 6 using 2-chloro-1-methylpyridinium iodide. 11.Process as claimed in claim 8, characterized in thatbis(4-methoxybenzyl)-3-hydroxycyclobutane-1,1-dicarboxylate is obtainedby reactingbis(4-methoxybenzyl)-3-tert.-butyldimethylsiloxycyclobutane-1,1-dicarboxylatewith tetrabutylammonium fluoride.
 12. Process as claimed in claim 11,characterized in thatbis(4-methoxybenzyl)-3-tert.-butyldimethylsiloxycyclobutane-1,1-dicarboxylateis obtained by reacting bis(4-methoxybenzyl)malonate with1,3-dibromo-2-tert.-butyldimethylsiloxypropane.
 13. Pharmaceuticalpreparation containing a platinum complex according to claim 1 as anactive ingredient, optionally together with common auxiliary substancesand/or pharmaceutical solvents.
 14. Use of a platinum complex as claimedin claim 1 for the treatment of cancer diseases.
 15. Process forproducing a pharmaceutical preparation for treating cancer diseases,characterized in that a compound as claimed in claim 1 is transferredinto a therapeutically acceptable solution.